The synthesis of enantiomerically pure 3‐aryl substituted indanones is developed using an enantioselective sulfoxide‐based Knoevenagel condensation/Nazarov cyclization procedure. After the reductive ...desulfonation of the methyl para‐tolyl sulfoxide‐containing chiral auxiliary under mild conditions, selected enantiomerically pure indanone is used for the divergent total syntheses of three resveratrol natural products (+)‐isopaucifloral F, (+)‐quadrangularin A, and (+)‐pallidol.
Sulfoxide mediators: Enantiomerically pure 3‐arylindanones are readily prepared in high yields via a methyl para‐tolyl sulfoxide‐containing chiral auxiliary by a Knoevenagel condensation/Nazarov cyclization/reductive‐cleavage procedure. The synthetic application of this methodology was illustrated in the divergent total syntheses of three resveratrol‐derived natural products (+)‐isopaucifloral F, (+)‐quadrangularin A, and (+)‐pallidol.
An efficient approach to obtain functionalized rhodanines was developed through a base-assisted one-pot coupling and continuous cyclization of a primary amine, carbon disulfide, and methyl ...(2-chloroacetyl)carbamate. This conversion tolerates a broad range of functional groups and can be used to scale the preparation of
-substituted rhodanines in excellent yields.
The discovery of IDO1 and HDAC1 dual inhibitors may provide a novel strategy for cancer treatment by taking advantages of both immunotherapeutic and epigenetic drugs. In this paper, saprorthoquinone ...(
) and 13 of its analogues from
Hance were investigated for their SAR against IDO1, the results demonstrated the
-quinone was a key pharmacophore. Then a series of IDO1 and HDAC dual inhibitors connected by appropriate linkers were designed, synthesized, and evaluated from the hit compound saprorthoquinone (
). Among them, compound
showed balanced activity against both IDO1 (IC
= 0.73 μM) and HDAC1 (IC
= 0.46 μM). Importantly, the structure of
suggested that an
-quinone pharmacophore and a
-(2-aminophenyl) amide pharmacophore were necessary for the IDO inhibition and HDAC inhibition respectively. Meanwhile, these two pharmacophore groups should be combined by a pentane linker. Moreover, the binding modes of
to the enzyme active site showed that the hydrogen bond with Leu234 of IDO1 appeared to confer increased potency to this class of inhibitors, which may explain the higher activity of
. This study provides a new strategy for future IDO1/HDAC dual inhibitors with synergistic antitumor activity started from lead compound
.
Antihypertensive agents are the most commonly prescribed class of medications in the United States. Evidence regarding the relationship between different types of antihypertensives and breast cancer ...risk is sparse and inconsistent, and prior studies have lacked the capacity to assess impacts of long-term use.
To evaluate associations between use of various classes of antihypertensive medications and risks of invasive ductal and invasive lobular breast cancers among postmenopausal women.
Population-based case-control study in the 3-county Seattle-Puget Sound metropolitan area. Participants were women aged 55 to 74 years, 880 of them with invasive ductal breast cancer, 1027 with invasive lobular breast cancer, and 856 with no cancer serving as controls.
Recency and duration of use of antihypertensive medications.
Risks of invasive ductal and invasive lobular breast cancers.
Current use of calcium-channel blockers for 10 or more years was associated with higher risks of ductal breast cancer (odds ratio OR, 2.4; 95% CI, 1.2-4.9) (P= .04 for trend) and lobular breast cancer (OR, 2.6; 95% CI, 1.3-5.3) (P= .01 for trend). This relationship did not vary appreciably by type of calcium-channel blocker used (short-acting vs long-acting, dihydropyridines vs non-dihydropyridines). In contrast, use of diuretics, β-blockers, and angiotensin II antagonists were not associated with risk.
While some studies have suggested a positive association between calcium-channel blocker use and breast cancer risk, this is the first study to observe that long-term current use of calcium-channel blockers in particular are associated with breast cancer risk. Additional research is needed to confirm this finding and to evaluate potential underlying biological mechanisms.
In view of the serious adverse reactions and clinical toxicity of first line therapy 5-fluorouracil and lack of small molecule therapeutics in colorectal cancer chemotherapy, a series of natural ...scaffold-based 3-arylindanone derivatives (9a-q) were designed, synthesized and evaluated as tubulin polymerization inhibitors targeting the colchicine site. The most potent colchicine binding site inhibitor (CBSI),
, exhibited 14-38 times more dominant anti-proliferative activity against three colon cancer cell lines than 5-fluorouracil. Particularly,
showed higher selectivity against human normal cells compared with 5-fluorouracil and colchicine, and displayed negligible cardiotoxicity through hERG assessment. Furthermore, the binding of
to the colchicine site was strongly supported by EBI competition assay and
inhibited more tubulin polymerization than colchicine. Besides, the mechanism of action and binding modes of
were verified by molecular dynamics simulations and docking. Therefore,
could be regarded as a promising CBSI for colorectal cancer therapy.
The 2014-2015 Ebola epidemic was considered to be the largest and most complex outbreak, which caused 11,310 reported deaths. The epidemic disease can cause a mental health crisis, however, there is ...only a small amount of scientific literature available related to this health issue so far. We evaluated the psychological symptoms of 161 participants including Ebola survivors and healthcare workers in Sierra Leone, analyzed the impact of job classification, education level on psychological status. We found that the order of total general severity index (GSI) scores from high to low was EVD survivors, SL medical staff, SL logistic staff, SL medical students, and Chinese medical staff. There were 5 dimensions (obsession-compulsion, anxiety, hostility, phobic anxiety, and paranoid ideation) extremely high in EVD survivors. GSI were associated with university education negatively. We believed our information is necessary to develop the comprehensive emergency response plan for emerging infectious disease outbreak.
Parabacteroides distasonis (P. distasonis) plays an important role in human health, including diabetes, colorectal cancer and inflammatory bowel disease. Here, we show that P. distasonis is decreased ...in patients with hepatic fibrosis, and that administration of P. distasonis to male mice improves thioacetamide (TAA)- and methionine and choline-deficient (MCD) diet-induced hepatic fibrosis. Administration of P. distasonis also leads to increased bile salt hydrolase (BSH) activity, inhibition of intestinal farnesoid X receptor (FXR) signaling and decreased taurochenodeoxycholic acid (TCDCA) levels in liver. TCDCA produces toxicity in mouse primary hepatic cells (HSCs) and induces mitochondrial permeability transition (MPT) and Caspase-11 pyroptosis in mice. The decrease of TCDCA by P. distasonis improves activation of HSCs through decreasing MPT-Caspase-11 pyroptosis in hepatocytes. Celastrol, a compound reported to increase P. distasonis abundance in mice, promotes the growth of P. distasonis with concomitant enhancement of bile acid excretion and improvement of hepatic fibrosis in male mice. These data suggest that supplementation of P. distasonis may be a promising means to ameliorate hepatic fibrosis.
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